Appetite-inhibiting compositions



United States Patent Ofiice g 3,357,885 APPETlTE-ENHHBITING COMPOSITIONSLarry Stein, Belmont Hills, Pa., assignor to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledJan. 16, 1963, Ser. No. 251,746 6 Claims. (Cl. 16755) This inventionrelates in general to compositions useful for'appetite inhibition, andin particular to compositions which inhibit appetite While exhibitinggreatly reduced side effects as compared with known appetite reducers.

It is now well recognized that weight control is most reliably effectedby control of food intake, and recent years have seen a wide variety ofapproaches to the basic problem of reducing food intake.

One of the most appealing approaches has been the search for a compoundin easily administered oral dosage form which would harmlessly reduceappetite to a level at which food intake was instinctively kept at thelevel commensurate'with regulated weight loss or for maintenance ofoptimum weight. Amphetamine and'various other phenethylamines such asmephentermine, methamphetamine, and phenmetrazine have been proposed forsuch'aweight-control pill, and have been partially successful; however,these have had undesirable side eflects, and their use has accordinglybeen limited to cases Where these side effects could be ignored ortolerated. Specifically, amphetamine and the other phenethylamine-typecompounds in appetite controlling dosages have been found to raise theblood pressure and to cause excitation. Also, these compounds have beenfound to have relatively short duration of activity.

As a most important facet of my discovery it has been found that theadministration of this appetite suppressant composition not only resultsin the potentiation of the appetite-inhibiting effect of amphetamine,permitting the use of a much lower relative dosage of this component,but also blocks the peripheral pressor effect of amphetamine on theblood pressure. As a concrete illustration of this advantage may benoted the following test data on'animals obtained experimentally:Femoral arterial blood pressure was recorded by means of a pressuretransducer and electronic recorder in a series of anesthetized rats. In4 rats, 0.5 mg./kg. of amphetamine administered intravenously increasedblood pressure by 27/18 mm. mercury (systolic and diastolic readings).In a second group of 4 rats, the administration of 5 mg./kg. of one ofmy antidepressants (a polymethylene indole) by intravenousadministration 30 minutes prior to like administration of amphetaminedid not increase blood pressure of the animals, although in both casesappetite was depressed.

Therefore it is a prime object of the invention to provide a noveltherapeutic composition capable of enhancing appetite suppression inmammals.

It is a second object of the invention to enhance said appetitesuppression Without a concurrent elevation in blood pressure of theanimal so treated.

It has now been found, therefore, that quite unpredictably one maycontrol appetite without such effects as mentioned by the use of anappetite reducing composition comprising essentially a phenethylamine asmore particularly illustrated below, and, as a second principalingredient, a member of a class of aminoalkyl polycyclic compoundsreferred to in the field of pharmacology as antidepressants. The termantidepressant as it has been employed herein serves to characterizethese substances as a functional class. The functional activity ofantidepressants has long been recognized as one of mood elevation orphysiological energizing action when they are employed by themselves orinpharmaceutical preparations. It has been found that when admixed witha known appetite inhibitor such as various phenethylamines they promotethe positive appetite suppressant effects and mute their negativepressor effects as demonstrated.

The phenethylamine component of my composition may be generallyrepresented by the following generic formula:

with Z representing hydrogen, or wherein Z and R may be concatenated toform the general structure:

(5 A O -/R: (CHi)ii-l lRa with n representing an integer from two tothree; X represents a substitutent such as hydrogen, halogen such aschlorine, bromine and the like, or trifiuoromethyl; R represents a loweralkyl group such as methyl or ethyl; R represents either hydrogen or amethyl group; R and R each represent a substituent such as hydrogen or alower alkyl group of up to about six carbon atoms such as methyl, ethyl,propyl, and the like.

With the employment of the dual-component therapeutic compositions ofthe above type, it is believed that the antidepressant substitutedalkylamino component of the formulation generally depicted above exertsome as yet not clearly understood effect on the appetite controllingcenter in the brain of mammals, causing them to react strongly to thephenethylamine component potentiated with such agents. However, it isnot my intent to be bound by this mode of operation as other efiiectsnot presently recognized may in fact be involved in the action of thedrug.

My invention recited therefore in its general product aspect involvesthe discovery that a combination of any of the known alkylaminosubstituted pharmaceutical com positions classed as antidepressants witha phenethylamine as illustrated above quite unexpectedly gives rise to apotent appetite suppressant agent substantially devoid of deleterioussideetfects. In a'more limited product aspect my discovery involves thecombination of a particular antidepressant not heretofore known to theart, but disclosed in Rice et al. patent application Ser. No. 147,190,filed Oct. 24, 1961, now U.S. Patent No. 3,282,942, and Freed et alpatent application Ser. No. 168,505, filed Jan. 24, 1962, now U.S.Patent No. 3,215,691, with the aforesaid phenethylamines to produce alike result.

The aforesaid novel antidepressant compounds disclosed in the copendingpatent applications referred to may be illustrated by the generalformula:

and the pharmaceutically acceptable salts thereof wherein X is a memberof the group consisting of hydrogen, halogen, lower alkyl, nitro, amino,hydroxy, and lower alkoxy; R and R are hydrogen or lower alkyl; m is aninteger of from zero to four; Am is a primary, secondary, or tertiaryamine radical containing up to about eight carbon atoms, and Drepresents a bivalent organic radical selected from the group consistingof polymethylene radicals containing about 5 to 13 carbon atoms and arylradicals of the formula:

The terms lower alkyl and lower alkoxy as employed in the abovedefinition of my preferred antidepressant component includes bothstraight and branched chain alkyl radicals of less than about sevencarbon atoms, such as methyl, propyl, etc. A particularly desirable andeffective member of this class of antidepressants as defined hereinaboveis a member wherein X represents hydrogen; R and R represent hydrogen;Am represents dimethyl amino; and D is part of a cyclooctyl moiety, andm is 1.

As to the pharmaceutically acceptable salts of those antidepressantmembers which are novel, these may include acid addition salts of bothinorganic'acids, i.e., hydrochloric for example, or organic, i.e.,acetic or propionic acids or compounds capable of forming such additionsalts.

An appetite inhibiting composition containing the abovecycloalkaneindole and a phenethylamine as generally described isespecially found to be efiective in that at doses of the order of 5mg./kg. they more than double the anti-hunger action of d-amphetamine bypositively potentiating its anti-hunger effect and negating itsvasopressor action. The utility of this combination in obese mammalssufiering from high blood pressure but desirous of weight reduction isinstantly obvious. The effect of the antidepressant component on thephenethylamine component may be summarized, to wit:

(a) To augment and prolong the appetite inhibiting effect of thephenethylamine given, thus permitting a reduction in the dose ofphenethylamine;

(b) To increase the loss in weight produced by amphetamine;

(c) To repress the vasopressor activity of amphetamine.

The invention in its most general process aspect may be described asresiding in the concept of reducing appetite in mammals byadministration, preferably in oral dosage form, of the novel appetitesuppressant composition herein broadly described. A preferred processaspect of the invention involves the concept of and actualadministration to mammals, of a novel appetite suppressant compositioncomprising as active constituents the combination of 1 to 99 parts of aphenethylamine such as methamphetamine with an aminoalkyl polycycliccompound presently recognized to exhibit the property of reducingdepression in animals making up the remainder of the active ingredients.

In one of its most preferred process aspects the invention involves theconcept and specific administration of a member of the particular classof N-(aminoalkyl) indoles or its pharmaceutically acceptable salts asdescribed above in combination with a phenethylamine to mammals toreduce appetite therein. When so administered the therapeuticallyeifective quantity or unit dosage of the appetite suppressant agent canvary over rather wide limits, depending upon the therapeutic effectdesired. In general the daily dosages per kilo of body weight can varyfrom about 5 to 200 mg. of the composition. Each unit dosage form of thenovel therapeutic composition can contain from about 5 to percent ofactive ingredients in the ratios above noted and preferably for mostrapid result from about 50 to 95 percent of the novel therapeutic agentsby weight of the entire composition with the remainder comprisingvarious pharmaceutical carriers.

By the term pharmaceutical carriers I intend to include thosenon-therapeutic materials which are conventionally used in unit dosageforms, and thus include various fillers, diluents, binders, lubricants,disintegrating agents, and solvents. It is of course to be understoodthat the novel composition may be administered without such carrier ifdesired, and may be administered either prior to or following the onsetof the condition treated.

Various pharmacologic procedures were carried out in test animals toevaluate the appetite inhibiting effect of these novel therapeuticagents. A convenient and effective means of demonstrating theeffectiveness of the compositions is illustrated in the followingspecific embodiment of my invention which illustrates its preferred modeof use and the advantages attained as a result of the, practice of suchmode. It is of course to be understood that the following examples arepurely for purposes of further illustrating the invention and may not beconsidered as definitive of its scope. For a proper legal definition ofwhat I consider my invention to be, attention may be directed solely tothe several appended claims. Unless otherwise indicated, quantities arein grams and parts are in parts by weight.

EXAMPLE 1 Food consumption test in rats The test herein describedmeasures behavior in rats. For this purpose, non-deprived rats are used;that is, a supply of regular laboratory chow is always available to theanimals. During the test, sweetened condensed milk is also madeavailable to them from modified gradulated pipettes; the volume of milkconsumed in a given time interval indicates the effect, if any, the drugunder study has on the appetite.

Sprague-Dawley strain laboratory white rats, aged about six months andweighing from about 250 g. to 600 g., were maintained in individualcages with laboratory chow and water always available to them. Duringthe test period each cage was also provided with a graduated milkdispenser containing sweetened condensed milk. For each rat there wasfirst determined the normal or control rate of milk consumption byobservation at 15 minute intervals over a period of minutes. On drugtest days the rats were injected intraperitoneally with test compound,and after 20 minutes, 0.5 mg./kg. of d-amphetamine sulfate was injectedintraperitoneally. Milk intake was then observed after 15, 30, 60, and120 minutes. The results are summarized in the following table:

Average Milk Intake (percent Drug and Dosage No. of of no drug control)Rats 15 min. 60 min.

A (5 30 28 73 B (5. 5 37 83 C (O. 30 63 91 Azl (3dimethylaminopropyl)-2,3-hexamethyleneidole hydrochloride.

B=11 (3 dimethylaminopropyl)-5,6-dihydro-11H-benzo- [a]carbaz01ehydrochloride.

: Amphetamine sulfate.

EXAMPLE 2 In an experiment similar to that described in Example 1, thepotentiation by N-(3-dimethylaminopropyl)- 2,3-hexamethyleneindole ofthe appetite suppressing effects of various drugs was compared. Theresults are summarized in the following table:

The absence of any significant appetite inhibiting effect ofN-(3-dimethylaminopropyl) 2,3-hexamethyleneindole by itself at a dosagelevel of 5 mg./kg. was shown by tests on 17 rats, as follows.

It is to be noted that in the 34 comparisons shown in the followingtable of drug with no drug, only nine cases occur showing. less appetiteunder influence of this drug, and the mean of comparable tests showsslightly increased appetite. Twenty out .of the 34 show increasedappetite, and 5 show no effect.

15 minute reading (cc. milk) GOminute reading (cc. milk) Rat No. N 0drug N-(3-dimethyl- No drug N-(3-dimethyl- (average azmincpropyD-(average aminopropyD- of 5 2,3-hexamethof 5 2,3-hexam'ethreadings)yleneindole readings) yleneindole s-I e) m -l v 15.0 17. 5 16. 6 17.512. 2 13.9 15. 7 13. 9 17. 5 16.2 20. 6 18. 6 8. 6 12. 6 10. 2 15.0 19.5 16. 9 19. 5 16.9 25. 0 25. 0 25. 0 v 25. 0 9. 1 9. 7 9. 8 9. 7 9. 911.1 9. 9 11.1 10. 1, 18. 7 18. 0 18. 7 24. 4 25.0 24. 9 25. 0 9.6 13.79.8 16.7 15. 0 16. 4 15. 0 l6. 4 17. 1 21. 9 19.8 25. 0 22.9 17. 7 25.025.0 20. 5 1,7. 1 a 21. 6 19. 5 16.2 13. 0' 20.0 13.0 6. 9 8. 9 8. 7 13.6 Mean 15. 3 16. 2 17. 1 17. 7

Although the above examples show the combination treatment with aphenethylamine-type drug and a 2,3- substituted N-(aminoalkyl) indoleadministered by intraperitoneal injections, these drug combinations maybe administered orally with comparable results.

In the foregoing general description of my invention there have beendescribed certain alkylaminoalkyl substi- 5 tuted polymethylene indolesrepresented by generic Formula II as antidepressant components of mynovel therapeutic composition. However, certain other knownanti-depressantagents which may be generally represented by the formula:

and acid salts thereof wherein B is selected from radicals of the groupconsisting of I S, S, S e and -OH2CH:

and A is selected from the group consisting of ff (CH2)3N(CH3)!dmonmmonm and 1TI.CHa

onicnNni with R representing hydrogen or methyl, may'equivalently beemployed as the antidepressant. The following examples will illustratesome of these.

EXAMPLE 7 The following example further illustrates-some furtherembodiments of appetite depressant therapeutic compositions within thescope of my invention and the test results obtained from animalevaluation:

1 Average Milk Intake N o. of (percent 0! no drug Drug and Dosage Ratscontrol) 15 min. 60 min.

hydrochloride.

0 d-Amphetamine sulfate.

EXAMPLE 8 Other data were obtained from a weight-loss test. Rats areinjected with 5 mg/kg. of the test drug, then 20 minutes later with 0.75mg./kg. of d -methamphetamine hydrochloride. The loss 'in weight 6hours, after the methamphetamine injection serves as the indicator ofactivity.

Drug and Dosage N0. of Rats Mean Weight Loss alter 6 hrs. (Gm) extremelyuseful in the field of veterinary medicine where control of appetite isdeemed to be desirable. As a still further use, my particularformulations are also of value in pharmacological evaluation of variouspharmaceutical agents possessing properties of inhibition of appetiteand weight control. From a consideration of the invention as generallydescribed and further particularized by the several illustrativeexamples set forth, it is to be understood that many other uses willbecome obvious to those skilled in the art.

What is claimed is:

1. An appetite controlling therapeutic composition which comprises apharmaceutically effective dose of (A) a compound of the groupconsisting of (l) a phenethylamine of the formula:

@ DIX-R3 and consisting of -C, CH2- and wherein Z when alone representshydrogen, and when concatenated with R forms therewith a heterocyclicring of the structure:

ak wherein ,n represents an integer from 2 to 3, to result in a compoundof the formula:

wherein R R R X and n each has the meaning defined hereinbefore, and (B)an aminolkylpolycyclic compound capable of alleviating depression inmammals and selected from the group consisting of (1) compounds of theformula:

and pharmaceutically acceptable salts thereof; wherein W is a memberselected from the group consisting of hydrogen, halogen, lower alkyl,nitro, amino, hydroxy and lower alkoxy; R and R are each substituentsselected from the group consisting of hydrogen and lower alkyl; m is aninteger of from 0 to 4; Am is selected from the group consisting ofprimary, secondary, and tertiary amine groups containing up to eightcarbon atoms, and D represents a bivalent organic group selected fromthe group consisting of:

(a) polymethylene groups containing 5 to 13 carbon atoms, and (b) arylof the formula:

(2) compounds having the formula:

and pharmaceutically acceptable acid salts thereof; wherein A isselected from the group consisting of:

wherein R represents a substituent selected from the group consisting ofhydrogen and methyl.

2. An appetite controlling therapeutic composition according to claim 1wherein the phenethylamine is amphetamine.

3. An appetite controlling therapeutic composition according to claim 1wherein the phenethylamine is mephentermine.

4. An appetite controlling therapeutic composition which comprises apharmaceutically effective dose of amphetamine and1-(3-dimethylaminopropyl)-2,3-hexamethyleneindole.

5. An appetite controlling therapeutic composition which comprises apharmaceutically effective dose of the pharmaceutically acceptablemineral acid salts of amphetamine and1-(3-dimethylarninopropyl)-2,3-hexamethyleneindole.

6. An appetite controlling therapeutic composition in unit dosage formwhich comprises 5 to 200 milligrams of a composition comprisingamphetamine sulfate and 1-(3-dimethylaminopropyl)-2,3-hexamethyleneindole.

References Cited UNITED STATES PATENTS 3,066,075 11/1962 Deutsch 167-S53,218,232 11/1965 Stein et a1 l67---55 SAM ROSEN, Primary Examiner.

F. CACCIAPAGLIA, Examiner.

1. AN APPETITE CONTROLLING THERAPEUTIC COMPOSITION WHICH COMPRISES APHARMACEUTICALLY EFFECTIVE DOSE OF (A) A COMPOUND OF THE GROUPCONSISTING OF (1) A PHENETHYLAMINE OF THE FORMULA: